Maternal RND3/RhoE deficiency impairs placental mitochondrial function in preeclampsia by modulating the PPARγ-UCP2 cascade
Maternal RND3/RhoE deficiency impairs placental mitochondrial function in preeclampsia by modulating the PPARγ-UCP2 cascade
复制标题
母体 RND3/RhoE 缺乏通过调节 PPARγ-UCP2 级联损害先兆子痫的胎盘线粒体功能。
DOI：
10.1096/fj.202002639rrr
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发表时间：
2021-06-01
期刊：
影响因子：
4.8
通讯作者：
Yue, Xiaojing
中科院分区：
文献类型：
--
作者：
Huang, Liping;Ma, Yanlin;Yue, Xiaojing
先兆子痫（PE）是一种危及孕妇生命的疾病，与严重的高血压、蛋白尿或多器官损伤有关。线粒体介导的胎盘氧化应激在PE的发病机制中起关键作用。然而，其内在机制仍有待揭示。在这里，我们确定Rnd 3，一个小的Rho GTd 3，调节胎盘线粒体活性氧（ROS）。我们发现，Rnd 3在从PE患者分离的原代滋养层细胞中下调。滋养层细胞中Rnd 3的缺失导致过量ROS产生、细胞凋亡、线粒体损伤和呼吸链质子泄漏。此外，Rnd 3过表达部分挽救了人PE原代滋养层细胞中的线粒体缺陷和氧化应激。Rnd 3与过氧化物酶体增殖物激活受体γ（PPAR γ）发生物理相互作用，并促进PPAR γ-线粒体解偶联蛋白2（UCP 2）级联反应。过氧化物酶体增殖物激活受体γ的强制表达可缓解Rnd 3介导的线粒体功能障碍我们的结论是，Rnd 3作为一种新的保护因子在胎盘线粒体通过过氧化物酶体增殖物激活受体γ-UCP 2信号转导和强调，下调Rnd 3是一个潜在的因素参与PE发病机制。
Preeclampsia (PE) is a life-threatening disease of pregnant women associated with severe hypertension, proteinuria, or multi-organ injuries. Mitochondrial-mediated placental oxidative stress plays a key role in the pathogenesis of PE. However, the underlying mechanism remains to be revealed. Here, we identify Rnd3, a small Rho GTPase, regulating placental mitochondrial reactive oxygen species (ROS). We showed that Rnd3 is down-regulated in primary trophoblasts isolated from PE patients. Loss of Rnd3 in trophoblasts resulted in excessive ROS generation, cell apoptosis, mitochondrial injury, and proton leakage from the respiratory chain. Moreover, Rnd3 overexpression partially rescues the mitochondrial defects and oxidative stress in human PE primary trophoblasts. Rnd3 physically interacts with the peroxisome proliferators-activated receptor gamma (PPAR gamma) and promotes the PPAR gamma-mitochondrial uncoupling protein 2 (UCP2) cascade. Forced expression of PPAR gamma rescues deficiency of Rnd3-mediated mitochondrial dysfunction. We conclude that Rnd3 acts as a novel protective factor in placental mitochondria through PPAR gamma-UCP2 signaling and highlight that downregulation of Rnd3 is a potential factor involved in PE pathogenesis.